Current radiotracers to image neurodegenerative diseases

The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer’s diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities. The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers.


Introduction
It is well recognized that increased life expectancy results in an increased frequency of neurodegenerative diseases. In the last two to three decades, the development of new diagnostic and therapeutic methods has been intensified in neurodegenerative diseases. Molecular radiopharmaceutical-based neuroimaging is a growing field and provides several new diagnostic methods to investigate and characterize neurodegenerative diseases during life. This review summarizes the facts for the most frequent neurodegenerative diseases from a nuclear medicine point of view. Furthermore, the review provides information on approved radiotracers and ongoing research activities in the development of new radiotracers for imaging neurodegenerative diseases as well as a short passage about the need for novel radiotracers.

Neurodegenerative diseasesimportant histopathological and clinical facts
Alzheimer's disease (AD) Alzheimer's disease (AD) is the most common neurodegenerative disease causing dementia in the elderly. Histopathological characteristics of this disease are a progressive accumulation of β-amyloid (Aβ) plaques and hyperphosphorylated neurofibrillary tau protein (tau). However, only approximately 50 % of the patients have solely Alzheimer's pathology. Many patients show additional pathologic changes related to other neurodegenerative diseases in autopsy studies (Alzheimer's Association report 2018 -https:// www.sciencedirect.com/science/article/pii/S1552526018300414). Along with the typical clinical features like memory impairment, especially in the semantic and episodic domain and the executive dysfunction (McKhann et al. 2011), atypical variants of AD exist. As such, posterior cortical atrophy (PCA) and logopenic variant primary progressive aphasia (lvPPA) are labeled as atypical AD, since the histopathological changes (i.e. Aβ and tau accumulation) in these neurodegenerative diseases determine the "typical" AD features, although the distributional pattern of the pathologic changes seems to be different (Crutch et al. 2012;Harris and Jones 2014). However, in both PCA and lvPPA a significant minority of cases showed other underlying pathologies than AD, e.g. Lewy bodies, transactive response DNA binding protein of about 43 kDa (TAR DNA-binding protein 43, TDP-43) proteinopathies, "pure" tauopathy or cerebrovascular disease (Crutch et al. 2012;Harris and Jones 2014) (Table 1). The core clinical features of patients with PCA are caused by a decline in visual processing and other posterior cognitive functions, e.g. space and/or object perception deficits, simultanagnosia or constructional dyspraxia (Crutch et al. 2017). The core clinical features of lvPPA are impaired single-word retrieval in spontaneous speech and naming as well as impaired repetition of sentences and phrases (Harris and Jones 2014).

Frontotemporal lobar degeneration (FTLD)
FTLD is a potpourri of clinically, histopathologically and genetically different disorders that become united due to predominant pathological involvement of the frontal and temporal brain regions. Three distinct clinical phenotypes of FTLD are recognized including a behavior/dysexecutive syndrome -the behavioral variant of frontotemporal dementia (bvFTD); language disorders -the primary progressive aphasia (PPA): semantic variant (svPPA) and non-fluent/agrammatic variant (nfvPPA); and motor disorders (amyotrophic lateral sclerosis, corticobasal and progressive supranuclear palsy syndromes).
In general, an individual FTLD disorder can be ascribed to different histopathologies such as tauopathy (FTLD-tau), TDP-43 proteinopathy (FTLD-TDP-43) and the FET protein family that consists of Fused in sarcoma, Ewing sarcoma and TATA-binding protein associated factor 15 proteinopathy (FTLD-FET) (Table 1). Here, some histopathology is more often seen in one than in another FTLD disorder (Harris and Jones 2014;Bang et al. 2015;Mackenzie and Neumann 2016). Thus, more than 70% of the patients with svPPA have TDP-43 proteinopathy. Over 50% of patients with nfvPPA Tiepolt et al. EJNMMI Radiopharmacy and Chemistry (2019) 4:17 have FTLD-tau, approximately 20% show TDP-43 proteinopathy (Harris and Jones 2014). Almost half of the patients with bvFTD have FTLD-tau (Pressman and Miller 2014) and more than 25% TDP-43 pathology (Bang et al. 2015). Of interest, tauopathies can be differentiated in at least 5 subtypes according to their molecular subtype (Mackenzie and Neumann 2016).

Parkinsonian syndromes
In Parkinson's disease (PD), a degeneration of the nigrostriatal system occurs causing a reduction of the neurotransmitter dopamine. Degeneration of dopaminergic neurons in the substantia nigra pars compacta is an inherent neuropathological sign of PD. Histologically, most patients suffering from PD exhibit intracellular accumulation of protein inclusions mainly constituted of α-synuclein (Lewy bodies). However, some patients with specific genetic forms of PD do not have Lewy body pathology and it   (Postuma et al. 2015). Important supportive criteria include response to dopamine replacement, unilateral onset, olfactory dysfunction and REM sleep behavior disorder (Berg et al. 2013;Postuma et al. 2015). Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multisystem atrophy (MSA) are classified as atypical parkinsonisms. Histopathologically, CBD and PSP belong to primary tauopathies while MSA, DLB and PD are characterized by a pathologic accumulation of α-synuclein protein (α-synucleinopathies). The clinical presentation of CBD can be subdivided into 4 phenotypes: corticobasal syndrome, behavior spatial syndrome, nfvPPA and PSP (Armstrong et al. 2013) demonstrating that the accuracy to diagnose CBD ante-mortem is still limited. Clinical core features of PSP are akinetic-rigid syndrome, postural instability or falls and supranuclear ophthalmoplegia (Bensimon et al. 2009). The most recent version of PSP criteria published by the Movement Disorder Society includes eleven clinical phenotypes of PSP (Ali and Josephs 2018). Overall, the clinical diagnoses of post-mortemvalidated PSP cases were correctly established only in 19% of cases at the first clinical visit, and in 71% of cases over the course of the disease (Respondek et al. 2013). Furthermore, an average of 24% of post-mortem histopathologically diagnosed cases of MSA, PD and CBD were, ante-mortem, falsely diagnosed as PSP (Respondek et al. 2013). Also, the occurrence of concomitant AD (in approximately 36%) or PD (in approximately 20%) pathologies in PSP patients is remarkable (Dugger et al. 2014).
Histopathologic characteristics of MSA are inclusions of misfolded α-synuclein in oligodendrocytes (Jellinger 2014). According to the clinical presentation, MSA is usually subdivided into a parkinsonian subtype (MSA-P) and a cerebellar subtype (MSA-C). For the clinical phenotype, autonomic failure is a core symptom which must be present to establish the diagnosis of MSA (Gilman et al. 2008).

Lewy body dementia pathologies
Dementia with Lewy-bodies (DLB) is an α-synucleinopathy, characterized by widespread accumulation of Lewy bodies and Lewy neurites in the brain-stem, limbic system and cortical areas (Braak and Braak 2000) and a higher percentage of DLB compared to PD patients with dementia (PDD) show Aβ deposits in histopathological examinations. Consequently, approximately 80% of DLB patients have a positive Aβ PET scan (Drzezga 2010) (Table 1)  However, "the likelihood that the observed neuropathology explains the DLB clinical syndrome is directly related to the severity of Lewy-related pathology, and inversely related to the severity of concurrent AD-type pathology" (McKeith et al. 2005).
More than 75% of PDD patients develop in the long term clinical course of the disease (Aarsland et al. 2003). PDD is characterized by an intracellular accumulation of α-synuclein (Lewy bodies). Approximately 15% of PDD patients show cerebral β-amyloid plaques (Lucero et al. 2015;Edison et al. 2008). Due to an overlap of clinical and morphological features there is a continuous debate (Friedman 2018) of whether DLB and PDD are the same disease with different phenotypic representation of Lewy body disease spectrum.

Huntington's disease (HD)
HD is an autosomal-dominant neurodegenerative disease caused by a single gene mutation (Kim and Fung 2014) i.e. a CAG repeat expansion in exon 1 of the huntingtin gene (MacDonald et al. 1993). This repeated CAG expression results in an abnormal toxic protein which is named Huntingtin. This protein is expressed in all brain cells and disturbs protein degradation as well as several other cellular processes, e.g. mitochondrial function, axonal trafficking or peripheral immune regulation (Kim and Fung 2014). The cerebral accumulation of hyperphosphorylated tau aggregates seems to be a further histopathological characteristic besides the accumulation of the mutated Huntingtin protein (Vuono et al. 2015). From the clinical perspective, HD is characterized by progressive motor symptoms, cognitive decline and neuropsychiatric disturbances (Kim and Fung 2014).

Role of PET imaging in neurodegenerative diseases
Currently, the classification of neurodegenerative diseases is in permanent change and progress. Predominantly, phenotypical definitions are increasingly substitutedat least in research settings-by classifications which include biomarkers for the underlying pathophysiological process and thus lead to a more biological definition of neurodegenerative diseases (Jack et al. 2018). This development is of great significance for nuclear medicine, as molecular imaging using PET tracers can provide biomarker information, e.g. [ 18 F]FDG as a biomarker of neuronal injury or Aβ PET as a biomarker of AD pathology (Barthel et al. 2015). Table 2 summarizes all radiotracers mentioned in the review with abbreviation and chemical definition.

Molecular imaging of neurodegeneration
Glucose is the energy supplier of the brain. In all neurodegenerative diseases, impairment of neuronal function and therefore reduced energy metabolism occur. [ 18 F]FDG ( Fig. 1) as a marker for neuronal injury can be used to detect this impairment, and it is well known that different neurodegenerative diseases show distinct patterns of reduced [ 18 F]FDG uptake (Hellwig et al. 2012;Barthel et al. 2015) (Table 3). However, the hypometabolic patterns of some neurodegenerative disorders overlap. Due to its broad availability and sufficient diagnostic accuracy, [ 18 F]FDG is currently the widely used radiotracer in imaging of neurodegenerative diseases in clinical routine.

Synaptic density PET
In neurodegenerative diseases as well as in a variety of other neurological and psychiatric diseases, a reduction of synaptic density occurs during the course of disease (Feng et al. 2009;van Vliet et al. 2009;DeKosky and Scheff 1990;Hamos et

Imaging of neuroinflammation
Many neurodegenerative diseases are also accompanied, if not -as some researchers believe (Krstic and Knuesel 2013) -caused by inflammatory processes which are mainly mediated by activated microglia. The 18 kDa translocator protein (TSPO) is upregulated in glial cells during inflammation (Albrecht et al. 2016) and, as such, a target for PET neuroimaging. [ 11 C]PK-11195 (Fig. 3a) is the most-studied TSPO radiotracer. However, it has a low brain penetrance and a high non-specific binding resulting in a poor signal-to-noise ratio (Albrecht et al. 2016;Ory et al. 2014 (Fig. 3a) have several advantages as compared to [ 11 C]PK-11195, like a higher signal-to-background-ratio. As a potential drawback, however, the interpretation of their uptake is confounded by the existence of three different binding affinities (low-affinity, high-affinity, and mixed-affinity binder) (Albrecht et al. 2016;Herrera-Rivero et al. 2015). Other targets for an indirect measure of neuroinflammation have been identified, e.g. cyclooxygenase 1, histamine 4 receptors, alpha7-nicotinic acetylcholine receptors, and others (Ory et al. 2014;Albrecht et al. 2016). Several PET tracers for these targets have been developed and optimized e.g., [ 11 C]KTP-ME (Fig. 3b) for imaging cyclooxygenase 1 and [ 11 C]JNJ7777120 (Fig. 3c) for imaging histamine 4 receptors (Ory et al. 2014;Albrecht et al. 2016). However, neuroinflammation is a highly complex process which is not fully understood and more recently published data on PET imaging of cyclooxygenase 1 or histamine 4 receptors are missing. Radiotracers targeting alpha7-nAChRs are described in below in the Cholinergic System Imaging section.

Dopaminergic system imaging
Dopamine is a neurotransmitter involved in movement, cognition, motivation and addiction. Because the dopaminergic system is crucially involved in the pathophysiology of parkinsonism, imaging of the dopaminergic system is of particular interest in diseases such as Parkinson's disease or variants of atypical parkinsonism. The PET tracer [ 18 F]FDOPA (Fig. 4a) is a structural analogue of L-DOPA which is a precursor of dopamine. By measuring the uptake of dopamine precursors, [ 18 F]FDOPA can be used to investigate the integrity of the dopaminergic system (Leenders et al. 1990 (Fig. 4a).
Most neurodegenerative Parkinsonian syndromes such as idiopathic PD, atypical PD and DLB are associated, in contrast to drug-induced parkinsonism or essential tremor, with a loss of presynaptic dopaminergic neurons. Thus, imaging of the integrity of presynaptic dopaminergic function enables to differentiate neurodegenerative Parkinsonian syndromes from essential tremor or drug-induced parkinsonism (Seibyl 2008). Further, imaging of the integrity of presynaptic dopaminergic function is useful to differentiate AD from DLB (Minoshima et al. 2004).
Imaging of postsynaptic D 2/3 receptors with selective radioligands such as [ 11 C]raclopride (for PET) and [ 123 I]IBZM (for SPECT) (Fig. 4b)   Cholinergic system imaging Autoradiographic data revealed a significant reduction of different compartments of cholinergic neurotransmission, like nicotinic acetylcholine receptors (nAChRs) in patients with AD, PD and DLB (Perry et al. 1995;Martin-Ruiz et al. 2000;Flynn and Mash 1986;Sihver et al. 1999). These data are in support of the cholinergic hypothesis a b Fig. 4 Chemical structures of radiotracers for imaging the dopaminergic system -targeting: a presynaptic structures and b postsynaptic receptors of geriatric memory dysfunction which assumes that cognitive declines are mainly caused by a reduction of acetylcholine in the synaptic cleft as a consequence of a reduction of nicotinic neurons (Bartus et al. 1982). In autoradiographic studies, reductions of the α4 subunit of the nAChR were detected in the range of 50-65% in moderate-severe stage AD (Sihver et al. 1999;Martin-Ruiz et al. 2000) and 30-50% in moderate stage DLB (Martin-Ruiz et al. 2000). In contrast, in-vivo PET/SPECT studies using α4β2 nAChR-targeting radioligands demonstrated reductions to a more variable degree. This can be at least partly explained by the fact that distinct methods for quantification (e.g. binding potentials, distribution volumes, distribution volume ratios) of α4β2 nAChR availability were used and by the fact that patients cohorts differed between studies in severity of disease ranging from mild to moderate stage of the disease (O'Brien et al. 2007;Sabri et al. 2008;Meyer et al. 2009;Kendziorra et al. 2011;Meyer et al. 2014;Sultzer et al. 2017;Sabri et al. 2018 (Horti et al. 2013;Meyer et al. 2014) (Fig. 5a). Results of the first applications in humans of these next-generation α4β2 nAChR-targeting PET radioligands such as ( (Sabri et al. 2015a(Sabri et al. , 2015bSabri et al. 2018;Wong et al. 2013;Coughlin et al. 2018aCoughlin et al. , 2018b. Especially, the faster kinetics with sufficient estimation of radiotracer binding within 90 min (Sabri et al. 2015a(Sabri et al. , 2015bWong et al. 2013;Coughlin et al. 2018aCoughlin et al. , 2018b is an advantage compared to the early-generation α4β2 nAChR PET ligands. Further advantages are: (a) for (−)-[ 18 F]Flubatine a small metabolization which allows quantification without metabolite correction (Sabri et al. 2015a(Sabri et al. , 2015b, (b) for [ 18 F]AZAN a greater specific binding compared to 2-[ 18 F]A-85380 ) and (c) for [ 18 F]XTRA higher distribution volumes in extrathalamic brain regions compared to the published data of [ 18 F]AZAN and (−)-[ 18 F]Flubatine, whereby a displacement study needs to clarify whether these higher distribution volumes are due to specific or nonspecific binding (Coughlin et al. 2018a(Coughlin et al. , 2018b. In addition to the α4β2 subtype, also α7 nAChRs should play an important role in the pathophysiologic processes, for instance, in AD (Bao et al. 2017). α7 nAChRs seem to mediate Aβ-induced tau protein hyperphosphorylation (Wang et al. 2003) and modulate immunological process in AD (Conejero-Goldberg et al. 2008) and probably, in other neurodegenerative diseases. First α7 nAChR-targeting PET radioligands i.e. [ 11 C]CHIBA-1001 and [ 18 F]ASEM (Fig. 5b) have been evaluated in humans (Ishikawa et al. 2011;Wong et al. 2014;Coughlin et al. 2018aCoughlin et al. , 2018b and other promising radioligands e.g. compared to healthy controls (HCs) and, further, a correlation between neocortical AChE activity and dementia severity (Bierer et al. 1995). Therefore, ante-mortem examination of VChAT and AChE activity could be also of interest in AD. A radioligand targeting VChAT is [ 123 I]IBVM (Fig. 5c) and radioligands targeting AChE are [ 11 C]MP4A and [ 11 C]PMP (Kuhl et al. 1996;Kuhl et al. 1999;Roy et al. 2016) (Fig. 5d). Furthermore, [ 18 F]FEOBV, a novel, very promising PET radioligand targeting VChAT has been developed and successfully applied in patients with AD and PD (Aghourian et al. 2017;Bohnen et al. 2019). Thus, using abovementioned radioligands, reduced activities of VChAT and AChE were demonstrated in various neurodegenerative diseases like AD, PD and DLB (Kuhl et al. 1996;Kuhl et al. 1999;Roy et al. 2016;Aghourian et al. 2017;Bohnen et al. 2019).

Monoamine system imaging
The vesicular monoamine transporter 2 (VMAT2) is a membrane protein that transports monoamines (e.g. dopamine or serotonin) into the presynaptic vesicles. [ 18 F]AV-133 (Fig. 6) is a PET radiotracer targeting VMAT2. In patients with PD, a reduced [ 18 F]AV-133 uptake was found in the basal ganglia, more pronounced in the putamen and contralateral to the predominantly affected side at onset (Gao et al. 2016). An accuracy in differentiating PD patients from HCs similar to that of DAT SPECT has been reported. Furthermore, [ 18 F]AV-133 PET data might better correlate to clinical characteristics than PET/SPECT imaging data of DAT (Hsiao et al. 2014).

Imaging of misfolded proteins β-Amyloid (Aβ) PET imaging
Aβ plaques are the histopathological hallmark of AD. Moreover, their appearance in the brain is an early, if not the causal event in AD. The most widely used Aβ-targeting   (Clark et al. 2012;Sabri et al. 2015aSabri et al. , 2015bCurtis et al. 2015). Other Aβ PET tracers, such as [ 11 C]AZD2184, [ 18 F]FIBT, and [ 18 F]NAV4694 (Fig. 7), are under clinical examination (Ito et al. 2014;Grimmer et al. 2018). Results of the first in humans studies revealed a fast kinetics of [ 11 C]AZD2184 and [ 18 F] FIBT, and a time-window of 40-60 min p.i. was determined as reliable to calculate standard uptake value ratios (SUVRs) (Ito et al. 2014;Grimmer et al. 2018 (Ito et al. 2014;Rowe et al. 2013) which principally might translate to a higher sensitivity in detecting subtle amyloid pathology.
Over the last few years, the clinical and research diagnostic criteria especially for AD (McKhann et al. 2011;Albert et al. 2011;Dubois et al. 2014;McKeith et al. 2017;Jack et al. 2018) but also for other neurodegenerative diseases have been revised (McKeith et al. 2017;Berg et al. 2013), resulting in an implementation of biomarkers such as Aβ PET or [ 18 F]FDG PET. However, the validation process of these biomarkers is still incomplete (Frisoni et al. 2017). Especially, clinical outcome and cost-effectiveness studies are still missing (Frisoni et al. 2017). As such studies are the decisive prerequisite for reimbursement within many healthcare systems, these PET imaging biomarkers are so far not regularly applied in clinical routine.

Tau PET imaging
Physiological tau is a phosphoprotein which stabilizes the microtubules. In the brain, six isoforms of tau exist with either three repeats (3R) or four repeats (4R) of the microtubules-binding domain (Buée et al. 2000). Aggregated tau proteins consist of posttranslationally modified tau isoforms, whereby specific phenotypes/neurodegenerative diseases are associated with specific tau deposits that differ in microscopic appearance and ultrastructure (Buée et al. 2000;Villemagne et al. 2015). Importantly, the same clinical tauopathy phenotype can be caused by different misfolded tau proteins and vice-versa (Villemagne et al. 2015). In general, aggregated tau proteins are mainly located intracellularly and therefore a complex target for PET imaging. Current tau radiotracers share β-sheet binding properties. Since other misfolded proteins have similar structures, high selectivity for aggregated tau proteins is necessary (Lois et al. 2018). This is of particular interest, as tau aggregates can be co-localized to Aβ plaques with much higher concentrations of Aβ plaques compared to tau deposits (Villemagne et al. 2015). First-generation tau PET radiotracers -[ 18 F]AV-1451, [ 11 C]PBB3, [ 18 F]THK5351 (Fig. 8) showed favourable kinetics and high affinity to the 3R/4R tau isoform combination which is typical in AD (Villemagne et al. 2015;Lois et al. 2018;Villemagne 2018). However, the limitation of the first-generation tau PET radiotracers are a   (Fig. 8), have been preclinically evaluated and demonstrated high affinity, selectivity and specificity (Lois et al. 2018). Preliminary clinical data, partially available as conference abstracts, are promising Barret et al. 2017;Bohorquez et al. 2016;Wong et al. 2018;Bohorquez et al. 2017;Betthauser et al. 2018 Barret et al. 2017). Noteworthy, preliminary data also suggest that [ 18 F]PI-2620 might not only be able to visualize the 3R/4R tau isoform combination in AD, but also the 4R isoform in 4R-tauopathies such as PSP/CBD (https://www.alzforum.org/ news/conference-coverage/next-generation-tau-pet-tracers-strut-their-stuff ). Although the available data on the second-generation tau PET radiotracers are encouraging, the usefulness of these radiotracers for research and clinical approaches remains to be demonstrated in larger clinical trials.

Imaging of other misfolded proteins
Following the recent success with bringing amyloid and tau PET tracers into humans, the desire for radioligands targeting other misfolded proteins like α-synuclein or TDP-43 is evident. However, developing PET radiotracers that target misfolded proteins beyond Aβ is challenging as these proteins (i) are mainly intracellularly localized, (ii) appear in a much lower concentration than Aβ plaques (Villemagne et al. 2015;Lois et al. 2018;Harada et al. 2018;Verdurand et al. 2018), and (iii) have β-sheet binding motives which are rather similar to those of amyloid aggregates. Despite intensive efforts to develop α-synucleinand TDP-43-targeting PET radiotracers, until now no suitable substance has been described (Mathis et al. 2017). The FET protein family consists of fused in sarcoma (FUS), Ewing sarcoma (EWS) and TATA-binding protein associated factor 15 (TAF15) and was first discovered as components of fusion oncogenes causing specific malignancies (Mackenzie and Neumann 2016). As DNA/RNA binding proteins, they are predominantly located in the cell nucleus and are involved in DNA/RNA metabolism as well as in the maintenance of genomic stability (Mackenzie and Neumann 2016;Svetoni et al. 2016). In approximately 5-10% of all FTLD cases, the intracellular inclusions are FTLD-Tau-and TDP-43-negative in immunohistochemical examination. But they can be labeled using FUS/EWS/TAF15 antibodies and are therefore classified as FTLD-FUS or FTLD-FET group (Mackenzie and Neumann 2016). Similar to α-synuclein and TDP-43, the existing literature does not reveal any reports regarding FTLD-FET targeting radiotracers. Considering the low prevalence of these diseases (FTLD-TDP is rare, FTLD-FET is even rarer), the search for suitable radiotracers targeting these proteins is so far less active.

Summary and conclusion
In the last two to three decades, a large number of novel radiotracers for direct and indirect imaging neurodegenerative processes and their underlying pathology have been developed. Several of them have been approved and are used in clinical routine for early and differential diagnosis as well as for evaluation of disease progression. Others are appreciated as valuable research tracers. However, the more pathological components of the different neurodegenerative diseases are discovered, the more new and interesting issues occur. Such issues are (i) the classification of neurodegenerative disorders in clinical routine, (ii) the identification of targets for possible new radiotracers, (iii) the identification of novel radiotracer targets, (iv) the accurate monitoring strategy of such therapy trials. Some of them could be answered by PET studies with new radiotracers. But as important as the development of new radiotracers seems to be, at the moment it is equally important to sum up our gathered pieces of knowledge, combine them and try to get a more comprehensive understanding of the entire spectrum of neurodegenerative disorders (Fig. 9).